Adding Chemo to RT Boosts PFS in Follicular Lymphoma

But no effect on overall survival

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Progression-free survival (PFS) was significantly improved when patients with stage I-II low-grade follicular lymphoma were treated with involved field radiation therapy (IFRT) followed by multi-agent systemic therapy rather than IFRT alone, according to an international randomized trial.

Note that there was no significant difference in overall survival (OS) between the groups at 10 years.

BOSTON -- Progression-free survival (PFS) was significantly improved when patients with stage I-II low-grade follicular lymphoma were treated with involved field radiation therapy (IFRT) followed by multi-agent systemic therapy rather than IFRT alone, an international randomized trial reported here showed.

Results from the TROG 99.03 trial, presented at the annual meeting of the American Society for Radiation Therapy (ASTRO), revealed that at 10 years, PFS was 59% in patients who received IFRT followed by cyclophosphamide, vincristine and prednisone (CVP) with or without rituximab (R-CVP). By comparison, PFS was 41% in patients treated with IFRT alone (P=0.033).

There was no significant difference in overall survival (OS) between the groups at 10 years, reported Michael MacManus, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia.

OS was 95% in patients given IFRT plus R-CVP and 86% at 10 years in patients treated only with radiation (P=0.40).

"Involved field radiation therapy followed by six cycles of R-CVP would be a reasonable choice for the standard of care in stage I-II follicular lymphoma," McManus told delegates. "Further followup is required to evaluate the effect of systemic therapy on OS," he added.

Low-grade follicular lymphoma has a long natural history, and relapse occurs in 50% or more of cases following radiation therapy, mostly in areas outside the treatment field, he said. It is estimated that almost 14,000 new cases of follicular lymphoma are diagnosed in the U.S. each year and that 2% of these are stage I-II.

While "the addition of chemotherapy, especially with rituximab, improves PFS," said Richard T. Hoppe, MD, from Stanford University, what remains to be determined is whether PFS improvement will translate into a survival advantage. If it doesn't, Hoppe predicted in his commentary following the presentation, the combined modality may be difficult to defend.

Patients who had disease staging with positron emission tomography (PET) also had superior PFS, he pointed out. Without PET disease staging, 19 out of 42 patients (45%) would have been under-treated, he added.

Completing the trial "was a remarkable achievement," Hoppe said, noting the many diagnostic and treatment changes over the study's 12-year patient accrual period. Among them, the radiation dose dropped from 30-36 Gy to 24 Gy and following a protocol amendment in 2006, rituximab was added to systemic therapy.

"The investigators are to be congratulated," he said.

The trial enrolled 150 patients from 21 centers in Australia, New Zealand, and Canada from February 2000 to July 2012. There was a median potential follow-up of 9.6 years with a "late" group median followup of approximately 4.5 years.

Eligibility criteria included:

Grades 1, 2, or 3a disease

Stage I or II disease confirmed by CT and bone marrow aspirate and trephine

Disease that could be safely treated within radiation therapy fields

Life expectancy of more than 5 years

A total of 75 patients were randomized to Arm A and the same number to Arm B. Study participants were stratified according to treatment center, disease stage, age (younger or older than 60 years) and whether or not they had undergone PET staging, which was optional.

Patients in Arm A received IFRT 30 Gy in 1.5-2 Gy fractions. Patients in Arm B received identical IFRT, followed by six cycles of systemic therapy with either CVP (59%) or R-CVP (41%).

Chemotherapy consisted of cyclophosphamide 100 mg/m2 IV, vincristine 1.4 mg/m2 IV, and rituximab 375 mg/m2 IV on day 1. Oral prednisolone 50 mg/m2 was given on days 1 through 5.

Although IFRT was the same in both treatment arms, patients with nodal disease received treatment of the nodal region with a craniocaudal margin of 5 cm with or without treatment of the uninvolved region, as determined by the radiation oncologist.

Treatment of an extranodal site was individualized by site with treatment of uninvolved nodes optional in stage 1AE. When the site was bulky (more than 5 cm diameter) radiation dose was boosted to 36 Gy.

If patients had experienced neutropenia in a previous cycle, granulocyte colony-stimulating factor (G-CSF) with filgrastim (Neupogen) was permitted.

After radiation therapy, response was assessed with CT. Additional patient follow-up was conducted with a review every 3 months for 2 years, and a review every 6 months for 5 years. After this, study participants received an annual review which included CT imaging to assess disease status.

More episodes of grade 2 or greater toxicity occurred in the patients receiving multi-modal therapy in Arm B. However, there were fewer transformations to high-grade lymphoma in this group (four versus 10 in Arm A).

The transformations included 12 diffuse large B-cell lymphomas, one not otherwise specified (NOS) and one Burkitt lymphoma.

Acute radiation toxicity was experienced in 148 patients with a single case of grade 3 pneumonitis occurring during chemotherapy. However, the most severe toxicities were seen in patients who received systemic therapy.

A total of 67 patients experienced grade 3 or 4 chemotherapy toxicity. Three patients developed severe neuropathy (grades 3/4) and one died. There was also one death from refractory anemia after treatment with IFRT R-CVP.

Some of the late/subacute toxicities included pain and lymphedema, gastroesophageal reflux disease and alopecia.

Funding for this study was provided by the Cancer Council of Victoria, Australia, the Australasian Leukaemia and Lymphoma Group, Amgen, and Roche. The study authors disclosed a number of relationships with industry including Amgen and Roche.

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